title: Structure of the bacterial deacetylase LpxC bound to the nucleotide reaction product reveals mechanisms of oxyanion stabilization and proton transfer.
abstract: The emergence of antibiotic-resistant strains of pathogenic bacteria is an increasing threat to global health that underscores an urgent need for an expanded antibacterial armamentarium. Gram-negative bacteria, such as Escherichia coli, have become increasingly important clinical pathogens with limited treatment options. This is due in part to their lipopolysaccharide (LPS) outer membrane components, which dually serve as endotoxins while also protecting Gram-negative bacteria from antibiotic entry. The LpxC enzyme catalyzes the committed step of LPS biosynthesis, making LpxC a promising target for new antibacterials. Here, we present the first structure of an LpxC enzyme in complex with the deacetylation reaction product, UDP-(3-O-(R-3-hydroxymyristoyl))-glucosamine. These studies provide valuable insight into recognition of substrates and products by LpxC and a platform for structure-guided drug discovery of broad spectrum Gram-negative antibiotics.
authors.affiliation: Global Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Clayton
authors.affiliation: Global Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klein
authors.affiliation: Screening and Protein Sciences, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Rickert
authors.affiliation: Global Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.affiliation: Screening and Protein Sciences, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Maria
authors.initials: M
authors.lastname: Kornienko
authors.affiliation: Screening and Protein Sciences, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Joan
authors.initials: J
authors.lastname: Zugay-Murphy
authors.affiliation: Global Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: John C
authors.initials: JC
authors.lastname: Reid
authors.affiliation: Screening and Protein Sciences, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Srivanya
authors.initials: S
authors.lastname: Tummala
authors.affiliation: Screening and Protein Sciences, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, New Jersey 07033.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Infectious Diseases, Merck Research Laboratories, Kenilworth, New Jersey 07033.
authors.forename: Lynn
authors.initials: L
authors.lastname: Miesel
authors.affiliation: Screening and Protein Sciences, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Lumb
authors.affiliation: Global Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486. Electronic address: stephen_soisson@merck.com.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Soisson
mesh_terms: D000581:Amidohydrolases / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000096:biosynthesis / Q000737:chemistry; D009227:Myristic Acids / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011522:Protons; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D009227:Myristic Acids; D011522:Protons; C052121:UDP-3-O-(3-hydroxymyristoyl)-N-acetylglucosamine; D014537:Uridine Diphosphate N-Acetylglucosamine; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase
keywords: Antibiotics; Escherichia coli; Lipopolysaccharide (LPS); LpxC; Protein Structure; UDP; X-ray Crystallography